- 作者：Kiyohiro Oshima ; Izumi Takeyoshi ; Hirofumi Tsutsumi ; Jun Mohara ; Shigeru Ohki ; Norimasa Koike ; Taro Nameki ; Koshi Matsumoto and Yasuo Morishita
- 刊名：Journal of Surgical Research
- 出版年：2006
- 出版时间：October 2006
- 年：2006
- 卷：135
- 期：2
- 页码：380-384
- 全文大小：194 K
Background
Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid to prostaglandin endoperoxide (PGG2). There are two isoforms of COX, namely constitutive COX-1 and inducible COX-2. It has been reported that COX-2 plays an important role in ischemia–reperfusion injury and that COX-2 mRNA and protein expression were up-regulated during cardiac allograft rejection. FK3311 is a suppressor of COX-2 activation. The purpose of this study was to evaluate the effectiveness of inhibiting COX-2 with FK3311 for the minimization of ischemia–reperfusion injury and for the improvement of donor heart function following transplantation in a canine model.Materials and methods
Adult mongrel dogs were used. After the measurement of hemodynamic parameters [cardiac output (CO), left ventricular pressure (LVP), and the maximum rates of increase and decrease in LVP (±LVdp/dt)], coronary vascular beds were washed out with a hypothermic (4°C) University of Wisconsin (UW) solution following cardiac arrest in response to cold (4°C) glucose–insulin–potassium solution. The heart was then excised and preserved in hypothermic (4°C) UW solution for 12 h. FK3311 (3 mg/kg) was administered intravenously to five dogs prior to reperfusion, while vehicle was administered intravenously to a control group (n = 5). After 3 h of orthotopic transplantation using cardiopulmonary bypass, the hemodynamic parameters were compared with preoperative values of the donor animals under the condition of 10 mm Hg right atrial pressure and 5 μg/kg/min dopamine support.
Results
The recovery rates of CO and ±LVdP/dt were significantly (P < 0.05) higher in the FK-treated dogs than in the controls (CO: 93 ± 6 versus 66 % ± 4 % ; +LVdp/dt: 125 ± 8 versus 77 ± 10 % ; and −LVdp/dt: 81 ± 7 versus 52 ± 6 % ; for FK-treated versus control dogs, respectively). The recovery rate of LVP was higher in the FK-treated dogs than in the controls (90 ± 5 versus 72 ± 5 % ), but this difference was not statistically significant. Immunohistochemical staining revealed that COX-2 expression was reduced significantly in the myocardium of FK-treated dogs compared with controls.
Conclusion
Hemodynamic parameters following transplantation were improved significantly in dogs treated with FK3311. Therefore, the inhibition of COX-2 improves transplanted cardiac function following long-term preservation.